"Nature": Fudan Yuan Peng and others discovered a new mechanism of cognitive decline in Alzheimer's disease patients!

Alzheimer's disease (AD) is a globally endemic neurodegenerative disease characterized by abnormalities in neural circuits and neural network connections, memory and cognitive decline, etc
.

Previous studies on AD have focused on synaptic reduction and cell death, and have suggested that these may be the cause of neurological dysfunction [1], but the specific mechanism of neurological dysfunction in AD patients is not clear
.

An important pathological feature of AD is the presence of significantly enlarged neurites, also known as dystrophic neurites, near Aβ plaques [2].

Because these neurites are derived from axons rather than dendrites, the researchers named them plaque-associated axonal spheroids (PAASs), but the function of PPASs remains unclear
.

Recently, a research team led by Jaime Grutzendler of Yale University published the latest research results on AD in the international top journal Nature [3].

They found that PAAS are an important contributor to dysfunction of AD-related neural networks, and these axonal spheroids act as current "absorbers" to inhibit action potential conduction, and the larger the volume, the stronger
the inhibition effect.

They also found that nerve overexpression of PLD3 leads to endocytic lysosomal accumulation and axonal spheroid enlargement, inhibiting action potential conduction, while knocking out PLD3 can reduce endocytic lysosomal number and axonal spheroid volume, and improve neural network function
in AD mode mice.

This study reveals that targeting endosomal lysosomal production pathways, or PLD3, in neurons may be effective measures
to improve AD-related cognitive decline.
Yuan Peng, a young researcher at Fudan University, and Zhang Mengyang and Tong Lei of Yale University, are co-first authors
of the paper.

Screenshot of the first page of the article

Let's take a look at how this research
unfolds.

In both AD patients and AD model mouse brains, Grutzendler's team observed the presence of many PAAS near amyloid plaques
.

Based on the average volume of each PAAS and the total volume of PAAS around the plaque, they estimated that each plaque could affect hundreds of axons on average, which could affect countless axons and neurons
connected to them due to the high abundance of amyloid plaques in the brains of AD patients.

PAAS are present near amyloid plaques

They then tagged neuronal axons in AD model mice with viruses and found that PAAS remained stable for up to several months, and most PAAS gradually grew larger over time, but some PAAS decreased or disappeared, suggesting that PAAS were not the result of axon degeneration, but a relatively stable structure
.

To investigate whether PAAS affects the function of neural circuits, they first simulated it with a computer and found that PAAS could be a current "absorber" that blocks or delays the conduction
of action potentials.

To verify this result, they developed a method to detect action potential conduction on individual axons by calcium imaging in the brains of living mice, and found that PAAS inhibited axonal action potential conduction, and the larger the volume of PAASs, the stronger the inhibitory effect
.

Since PAAS affects axonal signaling in close proximity, do they affect distant cerebral hemisphere connections?

So they developed a set of methods to detect the signal transduction rate between the cerebral hemispheres by calcium imaging on living mice, and found that compared with wild-type mice, the action potential signaling of AD mode mice was significantly delayed, suggesting that local action potential conduction abnormalities caused by PAAS may lead to long-distance signal conduction disorders between cerebral
hemispheres.

For us, the axon distance is longer, resulting in a higher
probability of encountering amyloid plaques and signal transduction abnormalities.
The researchers analyzed human brain autopsy samples and found that in the brains of patients with moderate to severe AD, the average number of PAAS near each amyloid plaque was higher and larger, suggesting that the number and size of PAAS may be important factors
affecting neural circuit connections and cognitive function in AD patients.

AD patients have a larger number and volume of PAAs in their brains

So what factors contribute to the increase in the size of PAASs?

They found that lysosome-associated membrane protein (LAMP1)-positive vesicles (ELPVs) gradually accumulated in PAAS as mice aged, and there was a correlation
between the presence of ELPV and the size of PPASs.

The results of electron microscopy showed that with the aging of mice, a variety of vesicle organelles including endosomes, polyvesicular bodies (MVB), endophatic lysosomes, autophagic endosomes, and autophagic lysosomes accumulated, which may reflect different stages
of lysosomal production and autophagy pathways.

Moreover, they found that smaller PAAS contained higher levels of cathepsin D and were acidic, which is characteristic of mature lysosomes, and as the volume of PAASs increased, their acidity and cathepsin D levels also decreased, suggesting that ELPVs accumulation was due to lack of sufficient lysosomal protease and acidic environment
.

ELPVs accumulation is associated with PAAS enlargement and cognitive decline

They found similar results in autopsies of human brains, and the size of PAAS and the abundance of ELPVs were inversely correlated
with the patient's cognitive function before death.

Therefore, the accumulation of ELPVs may promote the enlargement of PAASs, resulting in abnormal axon signaling and ultimately cognitive impairment
.
In a follow-up study, they found that the AD risk gene PLD3 mediated the accumulation of ELPVs and the increase
of PAASs.

PLD3 mediates the enlargement of ELPVs and PAASs

Next, they knocked out PLD3 in AD mode mouse neurons and found that knocking out at either 3 or 7 months resulted in a significant decrease in the number of ELPVs and the size of PAASs, and could increase axonal action potential conduction rates
.

Moreover, knocking out PLD3 in basal forebrain neurons of 7-month-old AD mode mice can improve neural network function
.

Knocking out PLD3 in AD mode mouse brains improves neural network function

Overall, this study found that in the brains of AD mode mice, special structures PAAS near amyloid plaques can inhibit axonal signaling, thereby affecting neural network function, and the volume of PAAS is a key factor in this process, lysosomal protein PLD3 plays an important role in this, and knocking out PLD3 can improve neural network function
in AD mode mice.

This study provides a new idea and target for the treatment of AD, that is, to improve neural circuit function
by targeting the endoplasmomal lysosomal production pathway or PLD3 of neurons.
It is worth mentioning that interventions may be effective
even in the later stages of the pathology of amyloid plaques.

References:

1.
Palop JJ, Mucke L.
Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks.
Nat Neurosci.
2010; 13(7):812-818.
doi:10.
1038/nn.
2583

2.
Tsai J, Grutzendler J, Duff K, Gan W-B.
Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches.
Nat Neurosci.
2004; 7(11):1181-1183.
doi:10.
1038/nn1335

3.
Yuan P, Zhang M, Tong L, et al.
PLD3 affects axonal spheroids and network defects in Alzheimer’s disease.
Nature.
doi:10.
1038/s41586-022-05491-6